By 2050 older people at risk for cognitive decline and Alzheimer's (AD) are predicted to reach 13 million and health care costs are borne by individuals, their families, and society at large. This project is motivated from our studies of th neurobiology of mild cognitive impairment (MCI) in the elderly derived, in part, from the current PPG. A burgeoning literature suggests that alteration in endosmal/lysosomal (EL) proteins occur even before the formation of the classic pathologic AD lesion, the neurofibrillary tangle (NFT), composed of polymers of the microtubule-associated protein, tau. NFTs occur first in the transentorhinal cortex (TEC) then spread to the entorhinal cortex (EC) layer II and then to the hippocampal formation (HF) CA1 neurons of the MTL. Our group has shown that endosmal/lysosomal rab GTPase genes are dysregulated in concert with the TrkB neurotrophic cell survival receptor gene in HPC CA1 neurons in MCI. Building on these findings, we propose to perform single cell expression profiling combined with site specific tau antibody neuronal labeling to test whether select rab GTPases gene expression are differentially regulated early during the evolution of TEC layer III NFTs prior to ether EC or HF in preclinical AD, prior to cognitive decline. We will examine whether select tau cytoskeletal isoforms and/or rabs are related to clinical diagnosis, memory tests specific to the TEC/EC/HF connectome, neuropathology, intraneuronal Ass deposition, apolipoprotein E genotype in preclinical AD. In addition, we will determine the mechanism(s) underlying EL alterations prior to cognitive decline. This timely, novel and powerful approach will transform our understanding of the contributions of ELs to the vulnerability of MTL neurons in preclinical AD. The project is well positioned to lay the groundwork for a wide range of potential interventions that are truly distinc from approaches currently under investigation and may suggest novel tau/EL biomarkers for the early diagnosis of dementia.